Table 4.
Gene (Chromosome) | Histone Subtype | Mutation | Frequency | Tumor | Molecular, Biologic and Clinical Features |
---|---|---|---|---|---|
H3F3A (1) | H3.3 | K27M | Up to 93% | DIPG and midline tumors | These mutations are restricted to midline gliomas (pons, thalamus, cerebellum, and spine). All K27M gliomas have a poor prognosis. Geneexpression profile of these tumors is similar to the expression profiles of tumors with a proneural/oligodendroglial phenotype. TP53 mutations and PDGFRA and TOP3A amplifications are frequent. |
HIST1H3B (17) | H3.1 | K27M | Up to 31% | DIPG | These mutations are highly specific for tumors localized in the pons (DIPG) and the gliomas displaying these mutations show better prognosis than those H3.3K27M-positive. Gene expression profile in these tumors is similar to the expression profiles in adult tumors with a mesenchymal/astrocytic phenotype. ACVR1 and BCOR gene mutations are frequent. Genomic alterations of chr1q and chr2 are frequent. |
HIST1H3C (6) | H3.1 | K27M | <3% | DIPG | Properties similar to HIST1H3B-mutated tumors. |
HIST2H3C (6) | H3.2 | K27M | <2% | DIPG | Properties similar to HIST1H3B-mutated tumors. |
H3F3A (1) | H3.3 | K27I | <1% | DIPG and midline tumors | Properties similar to H3.3K27M-mutated tumors. |
H3F3A (1) | H3.3 | G34R | 12–14% | HGG | H3.3G34R/V tumors are almost entirely restricted to the cerebral hemispheres (16% in this location), particularly parietal and temporal lobes, are found predominantly in adolescent and young adults (median 15 years) and have a longer overall survival compared with other H3 mutant tumors. These tumors have a higher mutational burden than K27M gliomas. At the molecular level, frequent co-occurring events are TP53/ATRX alterations, PI3K and MAPK pathway mutations, MGMT promoter methylation. Genomic alterations of chr14q24 and chr17p13.1 are frequent. |
H3F3A (1) | H3.3 | G34L | <2% | HGG | Properties similar to G34R-mutated tumors. |
DIPG: diffuse intrinsic pontine glioma; HGG: high-grade glioma.